Distinct T cell sub-clusters may serve as biomarkers for immune related adverse events
Authors: Ying Jing, Jingwen Yang, Leng Han
Journal: Cell Reports Medicine (2023)

Identifying biomarkers of irAEs is the prerequisite for maximizing clinical benefits of patients treated by immune checkpoint inhibitors. Bukhari et al.1Bukhari S. Henick B.S. Winchester R.J. Lerrer S. Adam K. Gartshteyn Y. Maniar R. Lin Z. Khodadadi-Jamayran A. Tsirigos A. et al.Single cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitors.Cell Reports Medicine. 2022; 4: 100868https://doi.org/10.1016/j.xcrm.2022.100868Abstract Full Text Full Text PDF Scopus (1) Google Scholar identified significant associations between different peripheral T cell sub-clusters and arthritis, pneumonitis, and thyroiditis. Identifying biomarkers of irAEs is the prerequisite for maximizing clinical benefits of patients treated by immune checkpoint inhibitors. Bukhari et al.1Bukhari S. Henick B.S. Winchester R.J. Lerrer S. Adam K. Gartshteyn Y. Maniar R. Lin Z. Khodadadi-Jamayran A. Tsirigos A. et al.Single cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitors.Cell Reports Medicine. 2022; 4: 100868https://doi.org/10.1016/j.xcrm.2022.100868Abstract Full Text Full Text PDF Scopus (1) Google Scholar identified significant associations between different peripheral T cell sub-clusters and arthritis, pneumonitis, and thyroiditis. Immune-related adverse events, induced by immune checkpoint inhibitors (ICIs), lead to substantial morbidity and mortality in patients and may temper the clinical benefits of these drugs.2Sullivan R.J. Weber J.S. Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies.Nat. Rev. Drug Discov. 2022; 21: 495-508https://doi.org/10.1038/s41573-021-00259-5Crossref Scopus (34) Google Scholar Given that irAEs may involve in any organ or system of human body, strong heterogeneity lies in irAEs, including incidence, time of onset, presentations, and mechanism of action.3Schneider B.J. Naidoo J. Santomasso B.D. Lacchetti C. Adkins S. Anadkat M. Atkins M.B. Brassil K.J. Caterino J.M. Chau I. et al.Management of immune-related adverse events in patients treated with immune checkpoint inhibitor Therapy: ASCO Guideline Update.J. Clin. Oncol. 2021; 39: 4073-4126https://doi.org/10.1200/jco.21.01440Crossref PubMed Scopus (0) Google Scholar Therefore, identifying irAE-predictive biomarkers is one of the major challenges surrounding irAEs,4Jing Y. Yang J. Johnson D.B. Moslehi J.J. Han L. Harnessing big data to characterize immune-related adverse events.Nat. Rev. Clin. Oncol. 2022; 19: 269-280https://doi.org/10.1038/s41571-021-00597-8Crossref Scopus (9) Google Scholar and the related achievement will enable mitigating irAEs and improving patient outcomes. Moreover, it could also promote development of prophylactic or therapeutic strategies for irAE management. Recent studies explored the irAE-predictive potential of some factors, such as gender5Jing Y. Zhang Y. Wang J. Li K. Chen X. Heng J. Gao Q. Ye Y. Zhang Z. Liu Y. et al.Association between Sex and immune-related adverse events during immune checkpoint inhibitor Therapy.J. Natl. Cancer Inst. 2021; 113: 1396-1404https://doi.org/10.1093/jnci/djab035Crossref PubMed Scopus (29) Google Scholar and usage of antibiotics.6Jing Y. Chen X. Li K. Liu Y. Zhang Z. Chen Y. Liu Y. Wang Y. Lin S.H. Diao L. et al.Association of antibiotic treatment with immune-related adverse events in patients with cancer receiving immunotherapy.J. Immunother. Cancer. 2022; 10: e003779https://doi.org/10.1136/jitc-2021-003779Crossref Scopus (10) Google Scholar More importantly, several studies revealed the essential roles of T cell activation in irAEs7Jing Y. Liu J. Ye Y. Pan L. Deng H. Wang Y. Yang Y. Diao L. Lin S.H. Mills G.B. et al.Multi-omics prediction of immune-related adverse events during checkpoint immunotherapy.Nat. Commun. 2020; 11: 4946https://doi.org/10.1038/s41467-020-18742-9Crossref PubMed Scopus (64) Google Scholar and demonstrated the potential associations between pathogenic T cells and any irAEs8Lozano A.X. Chaudhuri A.A. Nene A. Bacchiocchi A. Earland N. Vesely M.D. Usmani A. Turner B.E. Steen C.B. Luca B.A. et al.T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma.Nat. Med. 2022; 28: 353-362https://doi.org/10.1038/s41591-021-01623-zCrossref PubMed Scopus (45) Google Scholar or myocarditis.9Axelrod M.L. Meijers W.C. Screever E.M. Qin J. Carroll M.G. Sun X. Tannous E. Zhang Y. Sugiura A. Taylor B.C. et al.T cells specific for alpha-myosin drive immunotherapy-related myocarditis.Nature. 2022; 611: 818-826https://doi.org/10.1038/s41586-022-05432-3Crossref Scopus (5) Google Scholar,10Zhu H. Galdos F.X. Lee D. Waliany S. Huang Y.V. Ryan J. Dang K. Neal J.W. Wakelee H.A. Reddy S.A. et al.Identification of pathogenic immune cell Subsets associated with checkpoint Inhibitor-induced myocarditis.Circulation. 2022; 146: 316-335https://doi.org/10.1161/circulationaha.121.056730Crossref PubMed Google Scholar In this study, Bukhari et al.1Bukhari S. Henick B.S. Winchester R.J. Lerrer S. Adam K. Gartshteyn Y. Maniar R. Lin Z. Khodadadi-Jamayran A. Tsirigos A. et al.Single cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitors.Cell Reports Medicine. 2022; 4: 100868https://doi.org/10.1016/j.xcrm.2022.100868Abstract Full Text Full Text PDF Scopus (1) Google Scholar expand the spectrum of T cell sub-clusters associated with arthritis, pneumonitis, and thyroiditis by profiling T cells in blood samples from ICI-treated cancer patients. Bukhari and colleagues performed single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) to delineate molecular features of peripheral T cells from ICI-treated patient with irAEs affecting different organs. They collected blood samples from 24 patients in a discovery cohort before and during ICI treatment, among whom seven developed pneumonitis, four developed polyarthritis, and four developed thyroiditis. Patients with arthritis had significantly more Th1/2 CXCR3+GATA3+ cells and less Tn TCF7+LEF1+ cells and Tcm CXCR3+ cells at baseline than patients without irAEs. Flow cytometry analysis on another cohort (n = 16) confirmed the decrease of Tcm cells in ICI patients who developed arthritis. Patients with thyroiditis and pneumonitis had higher proportions of two CD4 T sub-clusters, Th17 KRT27+ cells and Th2 JUN+ cells, compared with patients without irAEs. In addition, the authors classified pneumonitis into chronic hyperintensity pneumonitis (CHP) and organized pneumonia (OP) based on chest CT scans and identified divergent enrichment of T cell sub-clusters in these two subtypes of pneumonitis. They observed higher proportions of Tcm CXCR3+ cells in patients with OP and more Tn TCF7+LEF1+ cells in patients with CHP. This result highlights the advantage of linking image data, transcriptomic data, and immune features in future irAE biomarker studies. Beyond discovery of novel links between T cell sub-clusters and irAEs, the authors also explored how these T cell sub-clusters contribute to the development of irAEs. They interrogated a GWAS catalog and identified that signature genes of Th1/2 CXCR3+GATA3+ cells and upregulated genes of T cells from patients with autoimmune disease overlap. In addition, differentially expressed gene (DEG) analysis on Th1/2 CXCR3+GATA3+ cells revealed elevated expression of inflammatory genes in arthritis groups, while DEG analysis on Tcm CXCR3+ cells suggested T cell suppression phenotypes in patients with no irAE. In summary, this study collected two independent ICI patient cohorts to identify potential predictive biomarkers for arthritis, thyroiditis, and pneumonitis (Figure 1). Considering challenges in collecting large cohorts of irAE patients, this study moves a step forward in the development of biomarkers for different kinds of irAEs. Future work is necessary to reveal the functional mechanisms of specific T cell sub-clusters resulting in irAEs in different organs. The authors declare no competing interests. Single-cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitorsBukhari et al.Cell Reports MedicineDecember 12, 2022In BriefBukhari et al. report that different subsets of T cells are associated with organ-specific immune-related adverse events of checkpoint inhibitors and that quantification and characterization of these populations of cells pre-treatment have the potential to serve as toxicity-specific predictive biomarkers. Full-Text PDF Open Access